Objectives ERBB pathway alterations present therapeutic targets in high grade endometrial cancer (EC), but efficacy can be limited by persistent co-activation of other ERBB binding partners. The efficacy of dual-inhibition MEK+pan-ERBB or BET+pan-ERBB in an ERBB2/ERBB3 amplified EC was investigated via 3D microcancer ex-vivo cell assay.
Methods Tumor was prospectively collected from a patient with stage IIIc1 serous EC. Whole exome, mRNA, and MatePair genomic characterization was performed. Tumor cells were grown in 3D culture and subjected to titrating drug treatments. Cell viability was determined by the CellTiter-Glo Luminescent Assay. Data transformation and dose-response curves were generated using GraphPad PRISM using the variable slope model. CalcuSyn software with the Chou-Talalay method analyzed drug interactions and synergy. Afatinib, binimetanib, and JQ1 were used to inhibit pan-ERBB, MEK1/2, BET, respectively. For translational relevance, inhibitory effect was defined as percent reduction in ATP from baseline at the physiologically achievable concentration (maximum plasma concentration (Cmax) value).
Results Sequencing revealed amplifications of ERBB2 (17q12), RAF1, c-myc, and ERBB3 (12q13.2) low-level gain. Inhibition of viability was moderate by single agents: Afatinib, binimetanib, JQ1, as shown by inhibitory effect values of 14.4%,47.8%, 8.8%, respectively at physiologically achievable concentrations (Cmax) of afatinib. Combinations demonstrated increasing inhibitory effect values: 99.7% for Afatinib+ binimetanib, and 99.5% for Afatinib+JQ1. Synergy was evidenced for both combinations by a combination index <1 (figure 1).
Conclusions Combined inhibition of pan-ERBB with inhibition of MEK or BET proteins synergistically suppress viability in patient-derived serous EC harboring ERBB amplifications.
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